tbuckley/cabot-search huggingface dataset:
Multiple anthropometric measures and proarrhythmic 12-lead ECG indices: A mendelian randomization study
Authors: Maddalena Ardissino, Kiran Haresh Kumar Patel, Bilal Rayes, Rohin K. Reddy, Greg J. Mellor, Fu Siong Ng
Journal: PLoS Medicine (2023)

Observational studies suggest that electrocardiogram (ECG) indices might be influenced by obesity and other anthropometric measures, though it is difficult to infer causal relationships based on observational data due to risk of residual confounding. We utilized mendelian randomization (MR) to explore causal relevance of multiple anthropometric measures on P-wave duration (PWD), PR interval, QRS duration, and corrected QT interval (QTc).Uncorrelated (r2 < 0.001) genome-wide significant (p < 5 × 10-8) single nucleotide polymorphisms (SNPs) were extracted from genome-wide association studies (GWAS) on body mass index (BMI, n = 806,834), waist:hip ratio adjusted for BMI (aWHR, n = 697,734), height (n = 709,594), weight (n = 360,116), fat mass (n = 354,224), and fat-free mass (n = 354,808). Genetic association estimates for the outcomes were extracted from GWAS on PR interval and QRS duration (n = 180,574), PWD (n = 44,456), and QTc (n = 84,630). Data source GWAS studies were performed between 2018 and 2022 in predominantly European ancestry individuals. Inverse-variance weighted MR was used for primary analysis; weighted median MR and MR-Egger were used as sensitivity analyses. Higher genetically predicted BMI was associated with longer PWD (β 5.58; 95%CI [3.66,7.50]; p = < 0.001), as was higher fat mass (β 6.62; 95%CI [4.63,8.62]; p < 0.001), fat-free mass (β 9.16; 95%CI [6.85,11.47]; p < 0.001) height (β 4.23; 95%CI [3.16, 5.31]; p < 0.001), and weight (β 8.08; 95%CI [6.19,9.96]; p < 0.001). Finally, genetically predicted BMI was associated with longer QTc (β 3.53; 95%CI [2.63,4.43]; p < 0.001), driven by both fat mass (β 3.65; 95%CI [2.73,4.57]; p < 0.001) and fat-free mass (β 2.08; 95%CI [0.85,3.31]; p = 0.001). Additionally, genetically predicted height (β 0.98; 95%CI [0.46,1.50]; p < 0.001), weight (β 3.45; 95%CI [2.54,4.36]; p < 0.001), and aWHR (β 1.92; 95%CI [0.87,2.97]; p = < 0.001) were all associated with longer QTc. The key limitation is that due to insufficient power, we were not able to explore whether a single anthropometric measure is the primary driver of the associations observed.The results of this study support a causal role of BMI on multiple ECG indices that have previously been associated with atrial and ventricular arrhythmic risk. Importantly, the results identify a role of both fat mass, fat-free mass, and height in this association.
PB2035: REGULATION OF THE EGR2/FASL SIGNALING PATHWAY IS POTENTIALLY MEDIATED BY E3 UBIQUITIN PROTEIN LIGASE 2 IN BONE MARROW CELLS
Authors: Bo Ke, Chenghao Jin
Journal: HemaSphere (2023)

Topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research Background: It is undeniable that E3 ubiquitin protein ligase harbors multifaceted properties to regulate number of cellular processes. Among them, the oncogenic potential of WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) has recently gained significant attention, however, its precise molecular function remains to be determined. We previously found the downregulation of WWP2 in aplastic anemia, a rare hematopoietic/bone marrow disorder. Aims: Herein, as a follow-up, we sought to investigate the hypothesis that WWP2 may have molecular genetic changes or abnormal molecular regulation in bone marrow (BM) HSCs, thereby affecting its downstream signaling pathways, resulting in hematopoietic failure in AA patients. Methods: BM cells derived from mince were transfected with WWP2 lentiviral over-expression and interference vectors. The apoptosis and proliferation of cells, and the expression of WWP2 and its downstream factors were detected. Results: The analysis showed that the inhibition of WWP2 decreased proliferative capacity and increased apoptosis of BM cells, whereas WWP2 overexpression rescued this effect. Considering the preponderance of WW domain proteins in the EGR2-mediated FasL apoptosis pathway, we next observed that suppression of WPP2 leads to increased expression of key regulatory proteins of EGR2/FASL pathway (EGR2, FASL, FADD), and pro-apoptotic proteins (caspase 3, caspase 8, caspase 9, and Bax). Conversely, inhibition of EGR2 attenuated the apoptosis effect induced by WWP2 suppression in BM cells. In addition, we performed Insilco modeling to confirm potential WWP2- EGR2 protein interactions. Thus, our in vitro analysis provided evidence that downregulation of WWP2 increases the expression of FASL and FADD, thereby activating caspase 8 and inducing caspase 3-associated apoptosis in BM cells. Summary/Conclusion: In future, in vivo validation may ensure WWP2 as a putative mediator of the EGR2/FASL pathway and as a potential therapeutic target in aplastic anemia. Keywords: Aplastic anemia
PB2003: REAL-WORLD TREATMENT PATTERNS OF PATIENTS (PTS) WITH HIGHER-RISK MYELODYSPLASTIC SYNDROME (MDS) IN A US REAL-WORLD EVIDENCE DATABASE (COTA)
Authors: Rami S. Komrokji, Leyla Hernandez- Donoso, Sejla Hodzic, Henry Owusu, Kevin Nolan, Claire Nourry, María Díez Campelo
Journal: HemaSphere (2023)

Topic: 10. Myelodysplastic syndromes - Clinical Background: Pts with higher-risk MDS have poor outcomes and are in need of better treatment options. Aims: To understand current treatment patterns/identify unmet needs of pts with higher-risk MDS in the US. Methods: This was a retrospective, descriptive analysis of deidentified secondary data from the COTA MDS real-world evidence database, which included pt-level curated electronic health record data (EHR) from centers across the US. Data were abstracted from EHRs using these criteria: inclusion of adults with IPSS-R intermediate (I)/high (H)/very high-risk (vHR) MDS on/after 01/01/2012, exclusion of pts with no diagnosis date/clinician notes or pts with concurrent malignancies. Follow-up was until the last recorded event (last visit/other cancer/death; data cutoff 06/2022). Results: Data from 640 pts were included in this analysis. See Table for baseline demographic data. Most pts with IR- (225/281, 80%) and HR-MDS (162/239, 68%) were treated at community centers; pts with vHR-MDS were equally treated at academic (59/120, 49%) and community centers (61/120, 51%). Genetic/molecular data were limited; among pts with data available, the most common genetic mutation was TP53 (75/215, 35%). Of 640 pts, 108 (17%) did not receive treatment and 110 (17%) received allogeneic stem cell transplant (alloSCT). Of those given systemic treatment, hypomethylating agents (HMAs) were the most common first-line treatment (444/532, 83%). Venetoclax was given to 35/640 pts (5%; as first line: 10/532, 2%; as second line: 20/170, 12%; as third line: 4/66, 6%). Median time to start treatment from diagnosis was 2.2, 1.1, and 0.9 mo for IR-, HR-, and vHR-MDS, respectively. Of 512 pts assessed for first-line treatment with duration data, treatment duration was 7.4, 5.4, and 4.2 mo for IR-, HR-, and vHR-MDS, respectively. In 340 pts—including pts who underwent alloSCT—with response data, pts with IR-, HR-, and vHR-MDS had RW response rates (any response) of 73%, 72%, and 58%, respectively. Median OS (mOS) from start of treatment was 29.0, 20.3, and 11.9 mo for IR-, HR-, and vHR-MDS, respectively. mOS (from treatment start) according to treatment: alloSCT 31.4 mo, chemotherapy 19.1 mo, HMAs 23.1 mo, investigational 22.1 mo, venetoclax 10.1 mo, and others 23.8 mo. About 20% of pts transformed into acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, or chronic lymphocytic leukemia. Summary/Conclusion: This real-world study showed that available treatment for pts with higher-risk MDS in the US is limited and remains a high unmet need.Keywords: MDS, Real world data, Hypomethylating agents
PB2255: ASSESSMENT OF CHEMOTHERAPY-INDUCED TOXICITY IN CHILDREN WITH HODGKIN LYMPHOMA RECEIVING THE EURONET PROTOCOL
Authors: Hala Bekhit, Louay Eldeeb, Emad Moussa, Sarah H Youssef, Nesreen Ali
Journal: HemaSphere (2023)

Topic: 17. Hodgkin lymphoma - Clinical Background: Safety data for vincristine, etoposide, prednisone, and doxorubicin (OEPA)-cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDAC) regimen from low-middle income countries (LMIC) are limited. Aims: We aimed to determine the tolerability of OEPA-COPDAC regimen in pediatric patients with Hodgkin lymphoma treated with the Euronet Protocol at Children’s Cancer Hospital Egypt. Methods: In a retrospective study, adverse events during OEPA and COPDAC cycles were assessed and graded according to the National Cancer Institute Common Terminology Criteria (CTC) version 5.0. The impact of acute toxicities on treatment delivery and hospital admission was also evaluated Results: Three hundred and one patients were eligible for the study; the male-to-female ratio was (2.6:1). The mean age at presentation was 10.1 years. Patients were assigned to three tumor groups (TG), i.e., TG1 (27.24%), TG2 (34.55%), and TG3 (38.21%). Of 1352 chemotherapy cycles scheduled for 301 patients, 1326 (98%) were successfully administered; toxicity was reported in 655 (49.5%) of the cycles. Acute toxicity occurred in 89% and 76% of the patients during OEPA1 and OEPA2, respectively. The frequency was much lower during COPDAC cycles, ranging from 15 to 30%. Neutropenia was the most common toxicity observed during OEPA, occurring in 256 patients (85%) and 211 patients (71%) during OEPA1 and OEPA2, respectively. Despite the high frequency of toxicity, treatment-related mortality (TRM) remained low; three patients (1%) died during OEPA cycles secondary to sepsis. Repeated toxicity, i.e., during two-thirds or more of the administered cycles, was observed at a higher frequency in children aged below five years. In addition, treatment modifications were higher in children below 5 years and above 15 years compared to those aged between 5 and 15 years. Summary/Conclusion: The OEPA/COPDAC regimen was well-tolerated and comparable to previous studies. Most of the toxicities occurred during OEPA cycles. The TRM was lower compared to published reports from LMIC, underscoring the importance of best supportive care practices in this group of patients. Keywords: Children, Hodgkin’s lymphoma, Chemotherapy toxicity
PB2272: PI3KΔ INHIBITOR LINPERLISIB FOR PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA: SUBGROUP ANALYSIS OF A PHASE 2 TRIAL
Authors: Lihua Qiu, Tingyu Wang, Xiuhua Sun, Hang Su, Junning Cao, Zhi-Ming LI, Yuqin Song, LI Zhang, Dengju LI, Huijing Wu, Wei Zhang, Junmin LI, Keshu Zhou, Hui Zhou, Yu Yang, Zhifeng LI, Hong Cen, Zhen Cai, Zhihui Zhang, Weijun Fu, Jie Jin, Fei LI, Weixin Wu, Xuekui Gu, Weiliang Zhu, Lihong Liu, Zengjun LI, Shuhua Yi, Lugui Qiu
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Linperlisib (YY-20394) is an oral PI3Kδ-selective inhibitor. In a multicenter phase 2 trial (NCT04370405), the efficacy and safety of linperlisib as third- or further-line treatment has been evaluated in patients with relapsed/refractory follicular lymphoma. The objective response rate (ORR) was 79.8% and the median progression-free survival (PFS) was 13.4 months. These compelling results have led to the conditional approval of linperlisib in China in 2022. Aims: This subgroup analysis aimed to separately analyze the efficacy and safety of linperlisib in patients with relapsed disease and those with refractory disease from this phase 2 trial. Methods: This phase 2 study enrolled 84 patients from 25 sites in China between April 2019 and September 2020, including 39 (46.4%) patients with relapsed-only disease and 45 (53.6%) patients with refractory disease. The refractory subgroup also included patients with both relapsed and refractory disease. All patients received oral linperlisib 80 mg once daily until disease progression, intolerable toxicity or withdrawal from the study. Response was assessed by an independent review committee according to the International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The primary endpoint was ORR. Results: The refractory subgroup had a shorter treatment time since diagnosis (median, 2.16 vs 4.03 years) and lower proportion of patients with at least three lines of prior therapies (73.3% vs 82.1%) compared with the relapsed-only group. All patients in both subgroups had received prior anti-CD20 antibody and alkylating agent. The ORR (73.3%, 33/45) in the refractory group was lower than that (87.2%, 34/39) in the relapsed-only group. The most common grade ≥3 treatment-related AEs were decreased neutrophil count (17.8%), infectious pneumonia (13.3%), and interstitial lung disease (6.7%) in the refractory group, and infectious pneumonia (25.6%) and decreased neutrophil count (12.8%) in the relapsed-only group (Table). Summary/Conclusion: The efficacy of linperlisib was numerically better in patients with relapsed follicular lymphoma than those with refractory follicular lymphoma. Grade ≥3 interstitial lung disease was relatively more common in patients with refractory follicular lymphoma.Keywords: PI3K, Follicular lymphoma, Phase II
PB2238: ATYPICAL CHRONIC MYELOID LEUKEMIA. CLINICAL AND MOLECULAR FEATURES. A SINGLE CENTER EXPERIENCE.
Authors: Javier Alberto Rojas Martínez, Marta García Culebras, Rosario María Morales Camacho, Elena Soria Saldise, Isabel Montero Cuadrado, Perez Simon Josè Antonio
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Atypical Chronic Myeloid Leukemia (aCML, according to ICC) or MDS/MPN with neutrophilia (according to the WHO- 5) is a rare hematological entity, included in the group of myelodysplastic/myeloproliferative syndromes. Diagnostic criteria are leukocytosis (with >10% immature granulocytes in blood), dysgranulopoiesis, no or minimal absolute basophilia, no or mininal absolute monocytosis, hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia and no meeting criteria for AML, other MDS/MPN and MPN. BCR::ABL1, PDGFRA, PDGFRB and FGFR1 rearrangement are absent. aCML can be associated with other cytogenetic changes including trisomy 8 and isochromosome 17q. Recurrent somatic point mutations of SETBP1, ASXL1, N/K-RAS, SRSF2, TET2, CBL, CSF3R and ETNK1 are the most common findings. No standard of care is currently available. Allogenic stem cell transplantation is the only curative strategy. Palliative drugs commonly used are AML-like chemotherapy, hypomethylating agents, hydroxyurea (HU), or PEG–IFN–α, ruxolotinib and trametinib. Aims: To describe the clinical and molecular features of a cohort of patients diagnosed with aCML in a single institution. Methods: Single center observational retrospective study. Genomic DNA was isolated using DNA kit from Qiagen. PCR-based targeted sequencing of 40 genes (Oncomine Myeloid Research panel) was performed using the Ion Torrent S5 sequencing platform from Life Technologies. Raw data analysis, alignments and variant calling were performed by Torrent Suite Software. Annotation and reporting were performed by using Ion Reporter. Interpretation of variants was made according to the recommendations of the ACMG. Results: The clinical features are presented in Table 1.The cytogenetic and molecular findings are described in Table 2. Patient 4 and 7 are omitted. Both of them had normal karyotype and targeted NGS was not available.Summary/Conclusion: Atypical Chronic Myeloid Leukemia, BCR::ABL1 negative (aCML) is a rare hematological entity, with a dismal prognosis. Molecular landscape is heterogenous. Further comprensive molecular profiling may allow to find new targeted treatments in the next future. In terms of improving the understanding of this disease, an european-wide registry and biobanks might be useful. Randomised controlled trials for this clinical condition are an urgent need. Keywords: Molecular, Molecular markers, Myeloid malignancies, Molecular cytogenetics
PB2395: ASSOCIATIONS BETWEEN GLYCOLYSIS PATTERNS AND IMMUNE CELL INFILTRATION IN THE TUMOR MICROENVIRONMENT IN DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS
Authors: Zhenyu Liu, Peipei Xu, Ying Du, Mengge Pan, Weilu Xu
Journal: HemaSphere (2023)

Topic: 20. Lymphoma Biology & Translational Research Background: As the most common B‑cell non‑Hodgkin lymphoma, diffuse large B‑cell lymphoma (DLBCL) remains over one‑third of the patients failing to achieve cure with initial treatment, hence the importance of a systematic and comprehensive understanding of DLBCL. Aims: To understand the relationship between glycolysis patterns and immune cell infiltration in the tumor microenvironment of patients with DLBCL. Methods: Based on 30 genes involved in glycolysis screened out of 72 glycolysis related genes in MCGDB database, we comprehensively evaluated the modification patterns of glycolysis in 564 DLBCL samples. Glycolysis patterns were subsequently associated with immune cell infiltration as well as disease prognosis in the tumor microenvironment. Results: Four glycolysis modification patterns were determined in the study，which were coincident with three immune subtypes of tumors regarded as immune-inflamed, immune-desert, and immune-excluded subtypes respectively. The immune-inflamed subtype was related with effective immune infiltration and better prognosis. The immune-excluded subtype was known as matrix activating and didn’t show a better prognosis. Lack of immune cell infiltration was observed in the immune-desert subtype, resulting in a poor survival. Summary/Conclusion: Our work revealed glycolytic modification patterns affect immune cell infiltration in the tumor microenvironment (TME) in DLBCL patients, suggesting that different glycolytic modification patterns could predict different outcomes, which will provide us with a better understanding for patients’ treatments. Keywords: DLBCL
PB2183: TRANSFUSION-RELATED COST OFFSETS AND TIME BURDEN IN PATIENTS WITH MYELOFIBROSIS (MF) TREATED WITH MOMELOTINIB (MMB) VS DANAZOL (DAN)
Authors: Lucia Masarova, Srdan Verstovsek, Tom Liu, Sumati Rao, Guatam Sajeev, Ryan Simpson, Weilong LI, Joseph Yang, Boris Gorsh, James Signorovitch
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: MF is a myeloproliferative neoplasm characterized by splenomegaly, debilitating symptoms, and bone marrow fibrosis. Transfusion-dependent (TD) anemia is present in one-quarter of patients at diagnosis and becomes more common as the disease progresses. TD imposes a high cost burden on healthcare systems with annual total medical costs up to ≈9 times higher for TD patients than for non-TD patients. MMB was assessed in previously JAK inhibitor treated, symptomatic, anemic patients with MF, ≈50% of whom were TD at entry in the phase 3 MOMENTUM trial (NCT04173494). MMB led to reduced transfusion burden compared with DAN and achieved durable transfusion independence (no red blood cell [RBC] transfusions 12 weeks prior and hemoglobin ≥8 g/dL). Aims: To estimate the projected differences in total medical service costs and time burden related to MMB vs DAN. Methods: Analysis was based on rates of TD (requiring ≥4 units of RBC transfusion in the 8 weeks before randomization), transfusion-independent (TI), transfusion-requiring (TR; requiring transfusions but did not meet the criteria for TD), and transfusion visits in MMB and DAN arms over 24 weeks from MOMENTUM. Projected cost offsets for MMB relative to DAN were calculated using these transfusion rates and cost estimates for TD vs TI/TR and transfusion visits from a previous economic analysis of patients with MF using the IBM MarketScan database (Gerds AT, et al. ASH 2022. Abstract 1729). Projected time savings were based on transfusion rates and time burden estimates for transfusion visits in patients with TD β-thalassemia (Knoth RL, et al. EHA 2022. Poster P1741). Results: Projected average annual total medical cost savings with MMB vs DAN was $53,143 per patient with baseline TD and $46,455 per patient with baseline TI/TR. Reduced rates of transfusion visits with MMB vs DAN were associated with annual outpatient transfusion cost savings of $16,520 per patient with baseline TD and $2,951 per patient with baseline TI/TR. Among patients who were TD at baseline, projected average annual savings in transfusion visit time associated with MMB vs DAN totaled 68 hours per patient (27 hours for preparation and waiting time, 32 hours for transfusion procedure and recovery, and 9 hours for travel time). Summary/Conclusion: Reductions in the rate of transfusion dependence and the number of transfusions required for MMB relative to DAN are associated with projected healthcare system cost savings in total medical and outpatient transfusion costs, and reduced projected transfusion-related time burden in these patients with MF.Keywords: Anemia, Myelofibrosis, Transfusion
PB2269: PI3KΔ INHIBITOR LINPERLISIB FOR ELDERLY PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA: SUBGROUP ANALYSIS OF A PHASE 2 TRIAL
Authors: Xiuhua Sun, Tingyu Wang, Lihua Qiu, Hang Su, Junning Cao, Zhi-Ming LI, Yuqin Song, LI Zhang, Dengju LI, Huijing Wu, Wei Zhang, Junmin LI, Keshu Zhou, Hui Zhou, Yu Yang, Zhifeng LI, Hong Cen, Zhen Cai, Zhihui Zhang, Weijun Fu, Jie Jin, Fei LI, Weixin Wu, Xuekui Gu, Weiliang Zhu, Lihong Liu, Zengjun LI, Shuhua Yi, Lugui Qiu
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Elderly patients have limited therapy strategies due to physical condition and tolerability. Although PI3K inhibitors have been conditionally approved for some indications, the treatment-related toxicities compromise their long-term use. Linperlisib (YY-20394) is a novel highly selective PI3Kδ inhibitor. A multicenter phase 2 trial (NCT04370405) has shown the promising antitumor activity and manageable safety profile of linperlisib as third- or further-line treatment in patients with relapsed/refractory follicular lymphoma. Aims: This subgroup analysis aimed to explore the efficacy and safety of linperlisib in the elderly patients from this phase 2 trial. Methods: This phase 2 study was conducted at 25 sites in China, and 84 patients with relapsed/refractory follicular lymphoma who had failed at least two prior systemic therapies were enrolled between April 2019 and September 2020. Linperlisib 80 mg was given orally once daily until disease progression, unacceptable toxicity or withdrawal from the study. Response was assessed by an independent review committee according to the International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The primary endpoint was objective response rate (ORR). In this subgroup analysis, elderly patients were defined as those aged ≥60 years. Results: There were 16 elderly patients in this study, with a median age of 66 years (range, 60-78). Eleven (68.8%) patients had stage IV disease by Ann Arbor stage. Thirteen (81.3%) patients received at least three lines of prior therapies. The ORR was 75.0% (95% CI, 47.6-92.7), with a median response duration of 9.2 months (95% CI, 3.0-not reached). The median progression-free survival was 11.2 months (95% CI, 5.5-not reached). The 1-year overall survival rate was 100% (Table). The most common grade ≥3 treatment-related AEs were infectious pneumonia (31.3%), increased lipase (12.5%), and interstitial lung disease (6.3%) Summary/Conclusion: For elderly patients, linperlisib also showed promising efficacy, which was similar to the results in younger patients. Infectious pneumonia needs attention in elderly patients, but the overall safety profile is manageable.Keywords: Follicular lymphoma, Phase II, PI3K